MK-208 is a guanidinothiazole derivative reported to be a potent H2 blocker devoid of antiandrogenic activity. Its potency and duration of action, in inhibiting pentagastrin-stimulated gastric secretion in man, was evaluated in this double-blind, five-way cross-over trial. Ten healthy male volunteers received single oral doses of placebo, cimetidine 300 mg, and MK-208 5, 10, and 20 mg. A continuous intravenous infusion of pentagastrin (1 microgram/kg/hr) was given 2-4 and 5-7 hr after each oral dose. Gastric contents were continuously aspirated and volumes and acid content determined every 30 min. Plasma levels for MK-208 and cimetidine were monitored over the 7 hr of the study. Cimetidine and all doses of MK-208 significantly inhibited gastric acid secretion in the initial 2-4 hr; however, 10- and 20-mg doses of MK-208 were significantly more potent than cimetidine. In the 5- to 7-hr period, cimetidine 300 mg was not different from placebo, while MK-208 in all doses studied continued to significantly suppress gastric secretion. Plasma levels for MK-208 showed dose-related increments. The results suggest that: (1) MK-208 is a potent inhibitor of gastric secretion in man, in a dose-related fashion at the doses tested; (2) under the study conditions, 5 mg MK-208 was equipotent to 300 mg cimetidine but with greater duration of action, extending at least 7 hr; and (3) these data suggest a future role for this new agent in therapy for acid-peptic disease in man.